Little in known about the mitogenic effects of estrogen (E) and progestins (P) in the postmenopausal breast. Despite this, hormones are commonly prescribed for postmenopausal hormone replacement therapy (HRT). We have developed an in vivo model of the postmenopausal mammary gland in mice and preliminary studies show that epithelial and stromal cells of the postmenopausal mammary gland of the mouse have a heightened sensitivity to the growth promoting effects of E and stromal cells in particular, have decreased expression of the growth inhibitor, TGF-Beta1 after estrogen treatment. The overall goals of this proposal are to characterize the hormonal responsiveness of the postmenopausal gland in mice to ovarian hormones and to elucidate the underlying mechanism(s). We hypothesize that in the mouse, altered hormonal responsiveness to estrogen may be due to either increased potency or efficacy of the hormone as a result of altered receptor function or an increase in receptor number, respectively. Furthermore, altered responsiveness to progestins, altered expression of growth factors (EGF, TGF-alpha, IGF-I, II) growth inhibitors (TGF-Beta1) and/or their respective receptors will also be investigated in the postmenopausal mammary gland, since interactions between estrogen and progestins and ovarian hormones and growth factors/inhibitors are also involved in growth regulation. To determine if a similar situation exists in the human, hormone receptor and growth factor/inhibitor, cellular distribution, as well as the effects of HRT on mammary cell proliferation and mammary gland morphology will also be analyzed in the postmenopausal human breast. The results obtained from the proposed studies should provide important information about the biology of the postmenopausal mammary gland and potential consequences of hormone replacement treatment in postmenopausal women.